1. Field of the Invention
The present invention relates to a solution polymerization process for making high molecular weight polymers containing phosphoester linkages, in particular those that degrade in vivo into non-toxic residues. The polymers made by the process of the invention are particularly useful as implantable medical devices and prolonged release drug delivery systems.
2. Description of the Prior Art
Polymers having phosphate linkages, called poly(phosphates), poly(phosphonates) and poly(phosphites), are known. See Penczek et al., Handbook of Polymer Synthesis Chapter 17: "Phosphorus-Containing Polymers", (Hans R. Kricheldorf ed., 1992). The respective structures of these three classes of compounds, each having a different side chain connected to the phosphorus atom, is as follows: ##STR2## The versatility of these polymers comes from the versatility of the phosphorus atom, which is known for a multiplicity of reactions. Its bonding can involve the 3p orbitals or various 3s-3p hybrids; spd hybrids are also possible because of the accessible d orbitals. Thus, the physico-chemical properties of the poly(phosphoesters) can be readily changed by varying either the R or R' group. The biodegradability of the polymer is due primarily to the physiologically labile phosphoester bond in the backbone of the polymer. By manipulating the backbone or the side chain, a wide range of biodegradation rates are attainable.
An additional feature of poly(phosphoesters) is the availability of functional side groups. Because phosphorus can be pentavalent, drug molecules or other biologically active substances can be chemically linked to the polymer. For example, drugs with --O-carboxy groups may be coupled to the phosphorus via an ester bond, which is hydrolyzable. The P--O--C group in the backbone also lowers the glass transition temperature of the polymer and, importantly, confers solubility in common organic solvents, which is desirable for easy characterization and processing.
The most common general reaction in preparing poly(phosphates) is a dehydrochlorination between a phosphorodichloridate and a diol according to the following equation: ##STR3## Most poly(phosphonates) are also obtained by condensation between appropriately substituted dichlorides and diols.
Poly(phosphites) have been prepared from glycols in a two-stage condensation reaction. A 20% molar excess of a dimethylphosphite is used to react with the glycol, followed by the removal of the methoxyphosphonyl end groups in the oligomers by high temperature.
A Friedel-Crafts reaction can also be used to synthesize poly(phosphates). Polymerization typically is effected by reacting either bis(chloromethyl) compounds with aromatic hydrocarbons or chloromethylated diphenyl ether with triaryl phosphates. Poly(phosphates) can also be obtained by bulk condensation between phosphorus diimidazolides and aromatic diols, such as resorcinol and quinoline, usually under nitrogen or some other inert gas.
High molecular weights have generally been possible by bulk polycondensation. However, rigorous conditions are often required, which can lead to chain acidolysis (or hydrolysis if water is present). Unwanted, thermally-induced side reactions, such as cross-linking reactions, can also occur if the polymer backbone is susceptible to hydrogen atom abstraction or oxidation with subsequent macroradical recombination.
To minimize these side reactions, the polymerization can also be carried out in solution. For example, Kobayashi et al., U.S. Pat. No. 4,923,951, teaches that a suitably-diluted concentration in the solvent should be chosen to prevent the viscosity of the reaction mixture from increasing so much that stirring becomes no longer feasible. See Kobayashi et al., column 5, lines 10-13. Solution polycondensation requires that both the diol and the phosphorus component be soluble in a common solvent. Typically, a chlorinated organic solvent is used, such as chloroform, dichloromethane, or dichloroethane. The solution polymerization must be run in the presence of equimolar amounts of the reactants and a stoichiometric amount of an acid acceptor, usually a tertiary amine such as pyridine or triethylamine. The product is then typically isolated from the solution by precipitation with a non-solvent and purified to remove the hydrochloride salt by conventional techniques known to those of ordinary skill in the art, such as by washing with an aqueous acidic solution, e.g., dilute HCl.
A wide variety of solution polymerization procedures have been proposed to influence the polymerization rate, the molecular weight or the physical form of the final polymer products of a polycondensation reaction. For example, one-stage low-solvent polymerizations have been used to increase the molecular weight of fluorine-containing polyimides (Vora, U.S. Pat. No. 4,954,609; 8-12% by weight monomers in inert solvent also produces narrow polydispersity for better processing) or to increase polymerization velocity in making alkylene oxide polymers (Tanaka et al., U.S. Pat. No. 3,876,564). Raising the temperature and water content of the reaction mixture in a two-stage polymerization has been used toincrease the molecular weight of poly(arylene thioether-ketone) compounds (Kawakami et al., U.S. Pat. No. 5,312,894).
A reaction medium comprising both a good solvent and a poor solvent has been used in the polymerization of epoxides to form granular polymers (Carville et al., U.S. Pat. No. 4,650,853), and the addition of a poor solvent, which comprises 30-60% by weight of the total solvent in a subsequent stage of polymerization, has been used to increase molecular weight in polyarylene sulfides (Tanaka et al., U.S. Pat. No. 5,130,411). Parekh, U.S. Pat. No. 4,417,044, discloses a process for making poly(etherimide) comprising (a) forming a prepolymer-solvent mixture; (b) removal of water, and thus solvent, to form a "prepolymer"; and (c) heating the "prepolymer" to form the poly(etherimide). See column 2, lines 29-44. In the second step, the continuous forming and reforming of a thin film typically permits the concentration of viscous materials. In the final process step, substantially complete polymerization, as well as the removal of both water and solvent, are said to occur. The second and third steps may be combined, for example, if the "prepolymer" is retained in a thin-film evaporator beyond the point at which a substantial portion of the solvent is removed, thus effecting what is described as "substantially complete polymerization." See column 7, lines 33-35 and 57-65.
Dellacoletta, U.S. Pat. No. 5,262,516, discloses a similar process for preparing a poly(etherimide)-poly(imide) copolymer by (a) forming an oligomer-solvent mixture; (b) removing unreacted organic diamine from the oligomer-solvent mixture; and (c) reacting an aromatic dianhydride with the oligomer in an inert, non-polar solvent. See column 2, lines 5-11. The second step, called a devolatilization process, is said to "fully" polymerize the oligomer to form a molten poly(etherimide) and, in the process, also removes solvent. See column 8, lines 60-63.
However, neither Parekh nor Dellacoletta suggest that solvent removal should be done to increase molecular weight. Further, none of the above variations has yet been applied to the formation of high molecular weight poly(phosphoesters).
Reaction times tend to be longer with solution polymerization than with bulk polymerization. However, because overall milder reaction conditions can be used, side reactions are minimized, and more sensitive functional groups can be incorporated into the polymer. The disadvantage of solution polymerization is that the attainment of high molecular weights, such as a molecular weight greater than about 10,000 to 20,000, is less likely.
Interfacial polycondensation can be used when high molecular weight polymers are desired at high reaction rates. Mild conditions minimize side reactions. Also the dependence of high molecular weight on stoichiometric equivalence between diol and dichloridate inherent in solution methods is removed. However, hydrolysis of the acid chloride may occur in the alkaline aqueous phase, since sensitive dichloridates that have some solubility in water are generally subject to hydrolysis rather than polymerization.
Thus, there remains a need for a polymerization procedure that will minimize the side-reactions usually obtained with the bulk polymerizations and/or polymerizations conducted at high temperatures thought to be necessary to achieve high molecular weights. At the same time, however, there is a need to provide significantly higher molecular weight materials than would be produced with a standard one-stage solution polymerization reaction.